Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells.
Nedd4 and Itch are E3 ubiquitin ligases that ubiquitinate similar targets in vitro and thus are thought to function similarly. T cells lacking Itch show spontaneous activation and T helper type 2 polarization. To test whether loss of Nedd4 affects T cells in the same way, we generated Nedd4(+/+) and Nedd4(-/-) fetal liver chimeras. Nedd4(-/-) T cells developed normally but proliferated less, produced less interleukin 2 and provided inadequate help to B cells. Nedd4(-/-) T cells contained more of the E3 ubiquitin ligase Cbl-b, and Nedd4 was required for polyubiquitination of Cbl-b induced by CD28 costimulation. Our data demonstrate that Nedd4 promotes the conversion of naive T cells into activated T cells. We propose that Nedd4 and Itch ubiquitinate distinct target proteins in vivo.
Yang
Baoli
B
Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
Gay
Denise L
DL
MacLeod
Megan K L
MK
Cao
Xiao
X
Hala
Tamara
T
Sweezer
Eileen M
EM
Kappler
John
J
Marrack
Philippa
P
Oliver
Paula M
PM
D000818:Animals; D018106:CD28 Antigens / Q000276:immunology / Q000378:metabolism; D056827:Endosomal Sorting Complexes Required for Transport; D005434:Flow Cytometry; D015151:Immunoblotting; D047468:Immunoprecipitation; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D000075702:Nedd4 Ubiquitin Protein Ligases; D050721:Proto-Oncogene Proteins c-cbl / Q000276:immunology / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D018183:Transplantation Chimera; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054875:Ubiquitination / Q000276:immunology*
D018106:CD28 Antigens; D056827:Endosomal Sorting Complexes Required for Transport; C471637:Itch protein, mouse; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618461:Nedd4l protein, mouse; D050721:Proto-Oncogene Proteins c-cbl; D044767:Ubiquitin-Protein Ligases